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Genetic counseling: Protein S Deficiency
Protein S Deficiency (pregnancy loss) Introduction and contracting *Introduction *What is your understanding about why you were referred for genetic counseling? *Do you have any questions or concerns you would like to discuss? *Address immediate concerns *Explain that we will be taking a detailed pregnancy and family history *Then we will answer your questions and talk a little more about protein S deficiency including how it is inherited and how it may increase the risk for pregnancy loss as well as other causes of multiple pregnancy losses Medical History *Who was referring physician *How many pregnancies have you had? *Confirm when the losses were and use EMPATHY *Why do you believe you had the miscarriages? *Sometimes women who have miscarriages are concerned that it might be due to something they did or did not do during the pregnancy *What were you told you about the pregnancy losses? *What types of testing did they do to find a reason for the miscarriages? *Were you sick at all during the pregnancies? *Did you drink, smoke or use drugs? *Any medications during the pregnancies *Did you take prenatal vitamins? *Any concerns about anything you might have been exposed to during any of your pregnancies? *Have you had any other chronic health problems except those due to the protein S deficiency? *Could you describe how you first found out you had protein S deficiency *Have you had any complications related to the protein S deficiency? Family History *Take a family history to see if there are any hereditary diseases that may run in your family that may or may not be related to your history of pregnancy losses *Miscarriages in other family members *Infertility *Mental retardation/learning difficulties *Birth defects (heart defects, CL/CP, spina bifida) *Chronic illnesses such as diabetes or heart disease *Anyone else with protein S deficiency *Any other blood clotting problems in the family *Sickle cell anemia *Specifically ask about symptoms of blood clotting see below *Consanguinity Psychosocial considerations and assessment *How are you handling the pregnancy losses? *Have family members or friends been supportive? *What do your plans for the future look like? *Are you currently working outside the home? *Are you in touch with a perinatal loss support group? *Would you like to be in touch with a support group? *Is your insurance covering the testing that has been performed? *Are there any other concerns or questions? Protein S deficiency What is protein S *A protein that is involved in stopping the blood clotting process *(Protein S is a vitamin K-dependent anticoagulant protein) *(Major function is as a cofactor to facilitate the action of activated protein C (APC) on its substrates, activated factor V (FVa), and activated factor VIII (FVIIIa) ) *(Normally forms a complx with protein C to inhibit coagulation) *Not having enough protein S may lead to problems with blood clotting in the veins (venous thromboembolism or pulmonary embolism in the lungs, but does not appear to increase risk for arterial thrombosis) *Also associated with increased risk for miscarriage (studies have focused mostly on miscarriages that occur in 2nd and 3rd trimesters) How does protein S deficiency occur (Inherited vs. Acquired) *Inherited risk factors *Caused by mutation in one of the two copies of the genes that instruct the body on how to make protein S (located on chromosome 3 at locus 3p11.1-q11.2 near a protein S pseudogene) *Discuss genes and AD inheritance *Incomplete penetrance (some individuals with protein S deficiency remain completely healthy and assymptomatic and there are other risk factors that may also contribute to the blood clotting in some individuals) *VTE develops in 60-80% of patients who are heterozygous for protein S deficiency. The remaining patients are asymptomatic, and some heterozygous individuals never develop VTE. *Occasionally a person can inherit two mutated copies *This results in purpura fulminans (characterized by small vessel thrombosis with cutaneous and subcutaneous necrosis, and it appears early in life, usually during the neonatal period or within the first year of life) *Acquired risk factors for thrombophilia *Age - 1 in 10,000 in young before age 40 and 1 in 1,000 in elderly *Malignancy -Tumor cells increase coagulant activity and so do chemotherapy drugs *Antiphospholipid antibodies - may be associated with lupus or other autoimmune disease and increases risk 9 fold *Surgery or major trauma-without prophylactic treatment risk may be as high as 45-70% with total hip or knee replacement surgery and increased risk continues for several weeks *Pregnancy -RR is 10 increases to 1 in 1,000 from 1 in 10,000 *HRT and oral contraceptives-- risk depends on estrogen content and type of progesterone some studies show 2-3 fold increase *Acquired thrombophilia *usually due to liver disease *vitamin K *systemic lupus erythematosus *Protein S levels decrease in pregnancy and can fall into the abnormal-low laboratory range, but the low levels of protein S in pregnancy do not cause thrombosis by themselves Special Concerns During Pregnancy *Pregnancy can result in falsely low protein S assays, especially functional assays. In addition, pregnancy increases the risk of thrombosis in patients who are heterozygous for protein S deficiency *A female patient who is on warfarin for prior thrombosis should not continue warfarin during pregnancy due to teratogenic effects *Heparin should be started during pregnancy and for 4-6 weeks postpartum in patients with protein S deficiency *One case control study suggested that fetuses with a prothrombotic risk factor may have an increased incidence of low birth weight, but only statistically significant when fetus carried multiple thrombotic risk factors or was homozygous for risk factors *Women with pre-eclampsia/eclampsia and intrauterine growth restriction, were more likely to have protein S deficiency than controls, but too small to assess strength of association *Feb 2002 article in Seminars in Perinatology stated that not all studies have found association between inherited thrombophilias and adverse pregnancy outcomes. It is limited by lack of well designed studies and therefore no clear evidence to determine when to test, whom to test, and what to test for Protein S deficiency and risk of miscarriage *French case control study of 232 instances of women experiencing stillbirth (> 22 weeks gestation) and 464 controls (cases were referred patients which may add bias because 84% had more than one stillbirth) *Independently protein S deficiency and factor V Leiden were correlated with stillbirth *MTHFR mutation frequency alone was no greater *However, with homozygosity for the MTHFR mutation plus an additional thrombophilic risk factor, and in the absence of supplementation with folic acid, the risk for stillbirth was 100% (28/28) *This study also confirmed that those with the assessed risk factors and stillbirth virtually always showed maternal vascular markers when the placenta was thoroughly evaluated *Study in Israel (May 2002) demonstrated among 40 women with unexplained intrauterine fetal death at >27 wks matched with 80 healthy women demonstrated significantly higher rate of protein S deficiency than controls (OR 3.2, 2.4-4.1 CI) biased sample may not be representative of women of other ethnicities *Prospective study in US of 145 patients with idiopathic pregnancy loss and 145 matched controls *1 or greater thrombophilic defect in 66% of study group and 28% of controls *21% of women with loss had combined thrombophilic defects compared to 5.5% controls *late pregnancy wastage more common in women with thrombophilia Prevention? *Individuals with homozygosity for the MTHFR mutation and any other predisposing factor (protein S deficiency, protein C deficiency, antithrombin III deficiency, the thrombophilic prothrombin mutation, factor V Leiden, or antiphospholipid antibodies), high dose folate supplementation beginning preconceptually may have a protective effect. *Those who have had one or more stillbirths and are found to have a thrombophilic mutation (not including MTHFR homozygosity in isolation) heparin and low dose aspirin may be appropriate Testing for Protein S Deficiency *Absent /reduced protein S and normal total proteins in heterozygote *Protein S antigen testing: *Functional protein S: *Assays for functional protein S are difficult to perform, indirect and are based on prolongation of blood clotting by the generation of APC and its function *Several other factors can alter the interpretation of test results falsely low protein S functional assay value can be observed in patients with factor V Leiden genetic defect and some pregnant women Incidence of Protein S Deficiency *based on 9000 blood donors 1 in 700 had protein S deficiency *unknown if deficiency varies by race, but thrombotic disease in general less frequent in Asians *No clear difference in male to female ratio Associated symptoms *Symptoms related to protein S deficiency include those associated with deep venous thrombosis (DVT), thrombophlebitis, or pulmonary embolus. *Venous thrombosis of the lower limbs: Lower limb swelling and discomfort are the usual symptoms. Occasionally, redness or discoloration also is present, with or without associated cellulitis. *A family history of thrombosis is an important finding, which suggests inherited thrombophilia. *Thrombosis at an early age (eg, usually <40 y) or recurrent thrombosis also is indicative of an inherited thrombophilic state (eg, protein S deficiency). *Deep vein thrombosis *The most common manifestation is venous thrombosis of the lower extremities (accounts for approximately 90% of all events) *Superficial veins that are thrombosed usually appear distended, firm, and noncompressible (cords), with or without associated redness or pain. *Superficial thrombophlebitis can be observed in some cases, with or without DVT *Classic presentation of DVT is a triad of calf pain, edema, and pain on dorsiflexion of the foot (less than a third of DVT cases exhibit these 3 findings) *Physicians observe unilateral leg or calf swelling with mild or moderate pain more often, which suggests DVT *Rarely, calf discomfort without swelling is the only sign of DVT *The differential diagnosis of DVT includes muscle strains and tears, passive swelling of a paralyzed or immobilized limb, Baker cyst, cellulitis, knee trauma or derangement, lymphatic obstruction, and the postphlebitic syndrome *Pulmonary embolism *Some patients may have associated or isolated pulmonary embolism and may experience dyspnea, chest pain, syncope, or cardiac palpitations *Classic pleuritic chest pain, cough, or hemoptysis suggests an embolism with pleural involvement *Acute right-sided heart failure occurs rarely and is associated with massive embolus *Findings of right ventricular dysfunction include bulging neck veins, a left parasternal lift, and an accentuated pulmonic component of the second heart sound. *These findings in the chest also are not specific for pulmonary embolism. Early Pregnancy Loss *establishing pregnancy is more difficult than many people realize *clinically recognized pregnancy loss occurs in ~15% of pregnancies *40-60% of all conceptions may be lost, but most of these (3/4) are estimated to be lost before it is recognized clinically *most miscarriages occur between 6-8 weeks and expulsion between 10-12 weeks *after 3 consecutive clinical abortions the empiric risk of aborting next pregnancy is 20-55% Late Pregnancy Loss *seem to be associated with thrombophilia Possible causes of pregnancy losses *chromosomal abnormalities (most common 70% of first trimester loss) **balanced translocation carrier (2.7-4.8% of couples with recurrent losses) **trisomies and other chromosomal anomalies *Hormonal causes **Inadequate luteal phase **Deficient progesterone *Endometrial factors (endometrial protein expression) *Uterine abnormalities **septate uterus **bicornate uterus **uterine myomas or fibroids **DES exposure in utero *Environmental exposures **Alcohol (women who drink 2X's week had sig. higher SA than other women but drinkers also tend to smoke also - possible confounding?) **tobacco ( if ½ pack a day or greater and appears to be dose dependent) **very heavy caffeine intake (moderate intake is not associated with SA) **chemical solvent exposure in either sex may increase risk *Immune Causes **autoimmune problems -- estimated to be cause of multiple SA's in up to 30% of women (woman makes antibodies that will attack her own proteins and those that she has in common with the fetus) o anticardiolipin antibodies -- type of a group of antiphospholipid antibodies that may be associated with miscarriage o circulating antibodies to cardiolipin and/or inappropriate coagulation parameters, plus poor reproductive outcome, SLE, or spontaneous thrombosis (the antibodies can react with phospholipids that are required for coagulation) o SLE - an autoimmune disease thought to be related to SA's (Antichromatin IgG is useful in diagnosing SLE antinuclear antibody testing can indicate many at risk for SLE or some other autoimmune diseases) **alloimmune causes -- (response to tissues from another individual of the same species) *Diabetes (controlled or unsuspected is not thought to cause SA) *Infection **chlamydia trachomatous causes acute and chronic infection of the endometrium which could interfere with implantation (more chlamydia antibodies in women with recurrent SA's but not all studies confirmed this) **Mycoplasma hominis and ureaplasma urealyticum (controversy over importance in losses) **CMV but suggests this is rare and causation not proven **Herpes simplex virus (importance in SA's debated) **HIV does not increase rates of loss in asymptomatic women *Psychological factors-two studies showed significant reduction in SA among women who have 3 or more SA's when undergoing counseling once per week during pregnancy Patient Resources *www.fvleiden.org (information of many thrombophilias and online support group) *support group for pregnancy loss (There is one at Christ hospital) References *Thrombophilia and the Genetic Counselor. Presentation by Liz Hellmann 2/5/02 *Maternal Fetal Medicine. Crese and Resnik. *Immunology May be Key to Pregnancy Loss. Carolyn Coulam M.D. and Nancy P. Hemenway. 1999. The InterNational Council on Infertility Information Dissemination, Inc. *Loss During Pregnancy or in the Newborn Period: Principles of Care with Clinical Cases and Analysis. Edited by J.R. Woods, Jr., MD and J.L. Esposito Woods, MBA.1997 Jannetti Publications, Inc Pitman NJ Notes The information in this outline was last updated in 2002. This material has been imported fom the wikibook "Genetic counseling"[ http://en.wikibooks.org/wiki/Genetic_counseling] under the GNU Free Documentation License.